Radical Reaction Forms Previously Inaccessible Alkene Coupling Products

Chemical groups containing oxygen, nitrogen, silicon, and other heteroatoms often react during alkene coupling reactions, generating undesirable product mixtures. But a new, iron-catalyzed radical reaction, developed by Phil S. Baran and coworkers at Scripps Research Institute, La Jolla, Calif., couples heteroatom-containing alkenes without all the messy side products (Nature 2014, DOI: 10.1038/nature14006). The heteroatom group remains unmodified while a carbon-carbon linkage forms in a highly controlled and predictable way.

About a year ago, Baran and coworkers developed a radical reaction in which an iron-based agent catalyzed the coupling of all-carbon alkene substrates (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja4117632). Although this method is useful and practical, the products it generates can also be obtained—albeit with difficulty, in some cases—from known reactions of nonalkene substrates such as alkyl halides, alcohols, and carboxylic acids.

The researchers have now identified a new iron-based catalyst that extends the scope of the reaction to heteroatom-containing alkene substrates. The paper shows 60 products, “90% of which have never been made before,” Baran says.

The extended reaction uses the new catalyst, a reducing agent, and a weak base to form C–C bonds that link heteroatom-substituted olefin “donor” substrates to “acceptor” alkenes bearing electron-withdrawing groups. The catalyst removes an electron from the donor, producing a radical that then combines with the acceptor.

A variety of readily available heteroatom-containing alkene donors can be used, including enol ethers, enamides, vinyl boronates, vinyl thioethers, vinyl silanes, and vinyl halides. The reactions work at ambient pressure, and no special precautions need to be taken to exclude air and moisture. To prove just how versatile the reactions are, Baran and coworkers showed that they could be run in a variety of commercial alcoholic beverages as solvents.

“It is surprising that the substrate scope of the reaction can be extended to such a wide variety of heteroatom-substituted olefins,” comments senior synthetic chemist Jonas Brånalt of AstraZeneca R&D, in Mölndal, Sweden, who uses the Baran group’s original all-carbon alkene reaction in his lab. “The new methodology will allow synthetic chemists to access novel structures that would be either difficult or even impossible to make using traditional synthetic routes.”

The approach “has the potential to shift the retrosynthetic paradigm,” says catalytic reaction specialist Michael J. Krische of the University of Texas, Austin. “It unlocks new possibilities for the construction of C–C bonds that are otherwise difficult to achieve, and its operational simplicity—the use of an inexpensive iron catalyst in ethanol solvent—makes it especially attractive.”

According to Baran, his team has some exciting follow-up plans: “Let me just say that this is the tip of the iceberg. There’s much more to come.”